Cancer has become the disease that poses the biggest threat to health of human beings in modern society. To date, many anti-cancer drugs available in the market are still cytotoxic drugs discovered in the last century, which kill a vast number of normal cells during tumor treatment, causing intolerable side effects to patients, and another intractable problem of drug resistance comes up as these drugs are extensively used.
Tumor vessel inhibition represents a new method developed in the late stage of last century for tumor treatment, and its research was based on the theory proposed by Folkman that survival, growth and metastasis of tumors rely on an extensive network of neovessels (Folkman. J. et. al. N. Engl. J. Med., 1971, 285, 1182-1186). It has been found in a large amount of clinical research that tumor tissues contain many neovessels, and growth and metastasis of tumor cells require a large number of vessels to supply sufficient oxygen and nutrients. Inhibition of neoangiogenesis in tumors can “starve” tumor cells to death, while inhibition of neovessels have little impact on normal cells because there are very few neovessels around normal cells which results in vessel inhibition-based anti-tumor drugs having characteristics such as high efficiency, safety and low toxicity.
Vessel inhibition may be classified into direct inhibition and indirect inhibition. Direct inhibition is an action on vascular endothelial cells to inhibit angiogenesis, extension and nutritional support to tumor cells of vessels. The main method currently used here is metronomic therapy with a cytotoxic drug, which can mitigate side effects of the cytotoxic drug but has difficulty in improving the damage caused by the drug to human bodies. Indirect inhibition suppresses neoangiogenesis by inhibiting angiogenic factors required for angiogenesis (Cao, Y. et. al. Int. J. Biochem. Cell Biol., 2001, 33, 357-369.). The process of angiogenesis includes activation of vascular endothelial cells under the action of an activator; secretion of proteases from the endothelial cells to degrade the basal membrane; migration and proliferation of the endothelial cells; formation of the lumen of neo-capillaries; and recruitment of pericytes to stabilize the peripheral structure of the neo-capillaries. Under physiological conditions there are two kinds of factors acting on angiogenesis, namely angiogenesis inhibitors and pro-angiogenic factors. Angiogenesis inhibitors may be categorized into two major types according to their functional specificity: one type is angiogenesis inhibitors specifically acting on endothelial cells, including angiostatins, endostatins and the like; and the other type is angiogenesis inhibitors non-specifically acting on endothelial cells, including cytokines, tissue metalloproteinase inhibitors, serine protease inhibitors, tumor suppressor gene products and the like. Pro-angiogenic factors include epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF) and the like (Hanks, S. K., et. al. FASEB, 1995, 9, 576-696). High-level expressions of various pro-angiogenic factors can be seen in different types of tumors, such as a high-level expression of EGF typically seen in epithelial cell tumors, and a high-level expression of PDGF typically seen in glioma. Current strategies for developing an anti-cancer drug against the tumor neoangiogenesis pathway mainly focus on increase in angiogenesis inhibitors and decrease in pro-angiogenic factors, wherein inhibiting high-level expressions of pro-angiogenic factors, especially by targeting the VEGF/VEGFR signaling pathway, has become the mainstream objective of current studies.
VEGF is a glycoprotein in human bodies and plays an important role in angiogenesis. The human VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and PLGF. VEGF can selectively act on VEGFR (VEGF receptor) which is a class of tyrosine kinase trans-membrane proteins. Binding VEGF to VEGFR changes the conformation of VEGFR, and results in dimerization of the receptor and also phosphorylation of intracellular tyrosine sites, thereby activating downstream transduction pathways (Joukov, V., et. al. EMBO J., 1996, 15, 290-298). Extensive studies show that the VEGF/VEGFR signaling transduction pathway is the most important pro-angiogenic and migration pathway in cells. By inhibition of this pathway, growth and migration of endothelial cells can be inhibited, and in turn the growth of tumors can be inhibited. Currently, several such drugs have been approved and more than 30 drugs are in clinical trials. One important drug is a recombinant humanized VEGF monoclonal antibody called bevacizumab (trade name Avastin), which is the first approved drug against angiogenesis in tumors and is capable of specifically binding VEGF-A to block the VEGF/VEGFR pathway. This drug achieved great success initially after its approval, but the problem of drug resistance gradually emerged from its long-term use. Further studies reveal that specific inhibition of VEGF-A causes cells to release a large amount of other pro-angiogenic factors such as PLGF and FGF, and such a phenomenon is called angiogenesis rescue reaction. To solve the drug-resistance problem, one possible strategy is to develop multi-target inhibitors.
Sunitinib is just a multi-target anti-cancer drug developed by Pfizer, which is an inhibitor acting on multi-target tyrosine kinases and can effectively inhibit receptor tyrosine kinases such as VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-13, and c-Kit, FLT-3. By inhibiting these proteins, sunitinib blocks expression of various pro-angiogenic factors in cancer cells, so that an objective to suppress neoangiogenesis and “starve” cancer cells to death can be realized (Abrams, T. J. et. al. Mol. Cancer Ther., 2003, 2, 1011-1021). Furthermore, sunitinib also shows direct specific inhibition against cancer cells having mutations in c-Kit and FLT-3. Sunitinib was approved by FDA in 2006, mainly for treatment of gastrointestinal stromal tumors and renal cell carcinoma, as the first anti-cancer drug approved for two kinds of indications at the same time. Although sunitinib shows remarkable anti-tumor efficacy, side effects such as lack of power, bone marrow depression and fever are still found in patients clinically administrated with sunitinib. Sunitinib shows strong accumulation in tissues and cannot be taken continuously, and in clinical scenarios its administration is performed successively for four weeks and is then stopped for two weeks. However, it is shown in research that neoangiogenesis in tumors recovers during the drug withdrawal. Therefore, it is necessary to modify the chemical structure to lower toxic side effects, optimize the druggability, and find safer and more efficacious medicaments.